Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) have been employed in human therapy. Almost all therapeutically useful opioids in the benzazocine and morphinane classes have a phenolic hydroxyl group (OH) at a position which is numbered “8” in the numbering system used for 2,6-methano-3-benzazocines [e.g., cyclazocine and EKC (ethylketocyclazocine)] and which is numbered “3” in the numbering system used for morphinanes (e.g., morphine).

Although the compounds of the present invention do not possess the furan ring of the morphinans, the morphinan numbering system will be used:

2,6-Methano-3-benzazocines are also known as benzomorphans, and this terminology will be used interchangeably herein.
Until the publications of Wentland et al[BioOrg. Med. Chem. Lett. 11, 623-626 (2001) and BioOrg. Med. Chem. Lett. 11, 1717-1721 (2001)] the uniform experience in the art of the past seventy years had been that removal or replacement of the phenolic 3-hydroxy group had led to pharmacologically inactive compounds.